phaidra.vetmeduni.ac.at o:4136 DOI 10.1016/j.kint.2025.01.024 Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease Chronic kidney disease (CKD) is a global health epidemic that greatly increases mortality due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiac injury in CKD. High serum levels of fibroblast growth factor (FGF) 23 in patients with CKD may contribute mechanistically to the pathogenesis of LVH by activating FGF receptor (FGFR) 4 signaling in cardiac myocytes. Mitochondrial dysfunction and cardiac metabolic remodeling are early features of cardiac injury that predate development of hypertrophy, but these mechanisms have been insufficiently studied in models of CKD. We found in wild-type mice with CKD induced by adenine diet, that morphological changes occurred in mitochondrial structure and cardiac mitochondrial and that metabolic dysfunction preceded the development of LVH. In bioengineered cardio-bundles and neonatal rat ventricular myocytes grown in vitro, FGF23-mediated activation of FGFR4 caused mitochondrial pathology, characterized by increased bioenergetic stress and increased glycolysis that preceded the development of cellular hypertrophy. The cardiac metabolic changes and associated mitochondrial alterations in mice with CKD were prevented by global and cardiac-specific deletion of FGFR4. Our findings indicate that metabolic remodeling and mitochondrial dysfunction are early cardiac complications of CKD that precede structural remodeling of the heart. Mechanistically, FGF23-mediated activation of FGFR4 causes mitochondrial dysfunction, suggesting that early pharmacologic inhibition of FGFR4 might serve as novel therapeutic intervention to prevent development of LVH and heart failure in patients with CKD. eng Animals Renal Insufficiency, Chronic Complications Renal Insufficiency, Chronic Metabolism Renal Insufficiency, Chronic Pathology Renal Insufficiency, Chronic Chemically Induced Fibroblast Growth Factors Metabolism Myocytes, Cardiac Metabolism Myocytes, Cardiac Pathology Fibroblast Growth Factor-23 Hypertrophy, Left Ventricular Etiology Hypertrophy, Left Ventricular Metabolism Hypertrophy, Left Ventricular Pathology Receptor, Fibroblast Growth Factor, Type 4 Metabolism Receptor, Fibroblast Growth Factor, Type 4 Genetics Receptor, Fibroblast Growth Factor, Type 4 Deficiency Disease Models, Animal Rats Male Mitochondria, Heart Metabolism Mitochondria, Heart Pathology Mitochondria, Heart Ultrastructure Mice Mice, Inbred C57BL Ventricular Remodeling Mice, Knockout Glycolysis Signal Transduction Cells, Cultured Adenine Energy Metabolism 2025-05-15T08:17:49.523Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Fuchs;Michaela A. A.; FN:Michaela A. A. Fuchs END:VCARD BEGIN:VCARD VERSION:3.0 N:Burke;Emily J.; FN:Emily J. Burke END:VCARD BEGIN:VCARD VERSION:3.0 N:Latic;Nejla; FN:Nejla Latic X-ORCID:https://orcid.org/0000-0001-5635-5175 END:VCARD BEGIN:VCARD VERSION:3.0 N:Murray;Susan L.; FN:Susan L. Murray END:VCARD BEGIN:VCARD VERSION:3.0 N:Li;Hanjun; FN:Hanjun Li END:VCARD BEGIN:VCARD VERSION:3.0 N:Sparks;Matthew A; FN:Matthew A Sparks END:VCARD BEGIN:VCARD VERSION:3.0 N:Abraham;Dennis; FN:Dennis Abraham END:VCARD BEGIN:VCARD VERSION:3.0 N:Zhang;Hengtao; FN:Hengtao Zhang END:VCARD BEGIN:VCARD VERSION:3.0 N:Rosenberg;Paul; FN:Paul Rosenberg END:VCARD BEGIN:VCARD VERSION:3.0 N:Saleem;Umber; FN:Umber Saleem END:VCARD BEGIN:VCARD VERSION:3.0 N:Hansen;Arne; FN:Arne Hansen END:VCARD BEGIN:VCARD VERSION:3.0 N:Miller;Sara E.; FN:Sara E. Miller END:VCARD BEGIN:VCARD VERSION:3.0 N:Ferreira;Davis; FN:Davis Ferreira END:VCARD BEGIN:VCARD VERSION:3.0 N:Hänzelmann;Sonja; FN:Sonja Hänzelmann END:VCARD BEGIN:VCARD VERSION:3.0 N:Hausmann;Fabian; FN:Fabian Hausmann END:VCARD BEGIN:VCARD VERSION:3.0 N:Huber;Tobias; FN:Tobias Huber END:VCARD BEGIN:VCARD VERSION:3.0 N:Erben;Reinhold G.; FN:Reinhold G. Erben END:VCARD BEGIN:VCARD VERSION:3.0 N:Fisher-Wellman;Kelsey; FN:Kelsey Fisher-Wellman END:VCARD BEGIN:VCARD VERSION:3.0 N:Bursac;Nenad; FN:Nenad Bursac END:VCARD BEGIN:VCARD VERSION:3.0 N:Wolf;Myles; FN:Myles Wolf END:VCARD BEGIN:VCARD VERSION:3.0 N:Grabner;Alexander; FN:Alexander Grabner END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 7019383 https://phaidra.vetmeduni.ac.at/o:4136 https://phaidra.vetmeduni.ac.at/api/object/o:4136/thumbnail LOMv1.0 discipline